Medicines: Commonly Used Dietary Supplements On Coagulation Function During Surgery

Medicines 2015, 2, 157-185; doi:10.
3390/medicines2030157
OPEN ACCESS
medicines
ISSN 2305-6320
www.mdpi.com/journal/medicines
Review
Commonly Used Dietary Supplements on Coagulation Function

during Surgery
Chong-Zhi Wang *, Jonathan Moss, Chun-Su Yuan
Department of Anesthesia & Critical Care, University of Chicago, Chicago, IL 60637, USA;
E-Mails: JM47@dacc.uchicago.edu (J.M.); CYuan@dacc.uchicago.edu (C.-S.Y.)
* Author to whom correspondence should be addressed; E-Mail: czwang@uchicago.edu;

Tel.: +1-773-702-0166; Fax: +1-773-834-0601.
Academic Editor: James D. Adams
Received: 30 May 2015 / Accepted: 22 July 2015 / Published: 27 July 2015
Abstract:
Background: Patients who undergo surgery appear to use dietary supplements

significantly more frequently than the general population. Because they contain
pharmacologically active compounds, dietary supplements may affect coagulation and platelet
function during the perioperative period through direct effects, pharmacodynamic
interactions, and pharmacokinetic interactions. However, in this regard, limited studies have
been conducted that address the pharmacological interactions of dietary supplements. To
avoid possible bleeding risks during surgery, information about the potential complications
of dietary supplements during perioperative management is important for physicians.
Methods: Through a systematic database search of all available years, articles were
identified in this review if they included dietary supplements and coagulation/platelet
function, while special attention was paid to studies published after 1990.
Results: Safety concerns are reported in commercially available dietary supplements. Effects
of the most commonly used natural products on blood coagulation and platelet function are
systematically reviewed, including 11 herbal medicines (echinacea, ephedra, garlic, ginger,
ginkgo, ginseng, green tea, kava, saw palmetto, St John’s wort, and valerian) and four
other dietary supplements (coenzyme Q10, glucosamine and chondroitin sulfate, fish oil,
and vitamins). Bleeding risks of garlic, ginkgo, ginseng, green tea, saw palmetto, St John’s
wort, and fish oil are reported. Cardiovascular instability was observed with ephedra,
Medicines 2015, 2 158
ginseng, and kava. Pharmacodynamic and pharmacokinetic interactions between dietary

supplements and drugs used in the perioperative period are discussed.
Conclusions: To prevent potential problems associated with the use of dietary

supplements, physicians should be familiar with the perioperative effects of commonly
used dietary supplements. Since the effects of dietary supplements on coagulation and
platelet function are difficult to predict, it is prudent to advise their discontinuation before
surgery.
Keywords: dietary supplements; natural products; surgery; coagulation; platelet

function; bleeding
1. Introduction
Complementary and alternative medicine (CAM) comprises health care practices that are not currently
considered an integral part of conventional therapies [1–3]. CAM covers a wide spectrum of ancient
to modern approaches that purport to expand options for preventing and treating diseases [4,5]. Some
people use CAM to relieve the side effects of conventional treatment or to enhance its effects [6,7].
Others use CAM as a means to increase their sense of control over health care [8,9].
While CAM offers patients more health care options, it is not without risks [10,11]. Not only can
CAM result in direct harm, but also the interactions between CAM and conventional medications may
delay necessary medical therapies [12,13]. Because knowledge of CAM is limited, in many cases, the
benefits and risks remain only partially understood. Studies have also confirmed that physicians and
other health care professionals have a poor knowledge of CAM [14,15].
Dietary supplements, including herbal medicine derived natural products, are a very commonly
used modality in CAM [16,17] and are often used by those who undergo surgical procedures. For
example, surgical patients appear to use herbal medicines significantly more frequently than the
general population. Tsen et al. reported that 22% of patients who underwent evaluation in a
preoperative clinic took herbs [18]. Kaye et al. found that 32% of patients in an ambulatory surgery
setting admitted to using herbal medications [19]. In a recent retrospective review, 23% of surgical
patients indicated the use of natural products, and older patients preferred dietary supplements [20].
Although the FDA has released Current Good Manufacturing Practices (CGMPs) for Dietary
Supplements [21], product variability exists between manufacturers. Because dietary supplements contain
pharmacologically active agents, they may affect blood coagulation and platelet function [22–24] through
several mechanisms, including direct effects (e.g., intrinsic pharmacologic effects), pharmacodynamic
interactions (e.g., alteration of the action of conventional drugs at effector sites), and pharmacokinetic
interactions (e.g., alteration of the absorption, distribution, metabolism, elimination, and toxicity of
conventional drugs). A relatively small number of studies have successfully addressed the pharmacological
interactions of herbal remedies [25,26]. Although limited, a pharmacokinetic analysis of the different
constituents in herbal remedies would be useful to clinicians [27,28].
Recommendations for the use of dietary supplements are often based on small clinical trials, case
reports, animal studies, or predictions derived from known pharmacology and expert opinions.
Research is essential because natural products are often widely adopted by the public before adequate
data support their safety and efficacy [29,30]. A mini review discussed the effects of herbal remedies on
the coagulation cascade, however, most information in the article relied on in vitro evidence [31].
In this article, we do not present a comprehensive review of dietary supplements. Rather, we
consider specific components relevant to the effects of natural products on hemodynamics, coagulation
and platelet function, focusing primarily on the most commonly used herbal medicines and other
dietary supplements based on two comprehensive CAM surveys in the United States.
2. Methods
2.1. Database and Search Strategies
A systematic search was performed in PubMed, SciFinder and Web of Science (1970–2014), with
the following terms: (natural product or herbal medicine or dietary supplement or selected natural
products) and (coagulation or platelet function or perioperative care). All of those searches ended
before December 2014, while special attention was paid to studies published after 1990. In addition,
we also performed manual searches in related textbooks and recent surgery and alternative medicine
journals. If necessary, further searches were conducted based on information in important references.
2.2. Fundamental CAM Information from Two Surveys in the U.S.
To evaluate whether CAM has become an integral part of American health care, the National
Institutes of Health conducted two comprehensive surveys in 2002 and 2007. In the 2002 survey,
36.0% of 31,044 adults interviewed had used some form of CAM in the previous 12 months [32]. In
the 2007 survey, 38.3% of 23,393 adults interviewed had used CAM in the previous year [33]. In the
2007 survey, the most commonly used CAM included natural products (17.7%), deep breathing
exercises (12.7%), meditation (9.4%), chiropractic or osteopathic manipulation (8.6%), massage
(8.3%), and yoga (6.1%). Between 2002 and 2007, the use of acupuncture, deep breathing exercises,
massage therapy, meditation, and yoga increased [33].
2.3. Selection of Monographs of Natural Products in this Review
The most commonly used CAM modalities are natural products, e.g., herbal medicines and other
dietary supplements [33]. The top ten herbal medicines are echinacea, ginseng, combination herb pills,
ginkgo, garlic, green tea, saw palmetto, soy isoflavones, grape seed extract, and milk thistle. The top
ten dietary supplements include fish oil or omega 3 or DHA, glucosamine, flaxseed oil, chondroitin,
coenzyme Q10, fiber or psyllium, cranberry, melatonin, methylsulfonylmethane (MSM), and lutein [33].
After considering the products that have shown the greatest impact on perioperative patient care,
eleven herbal medicines (echinacea, ephedra, garlic, ginger, ginkgo, ginseng, green tea, kava, saw
palmetto, St John’s wort, and valerian) and four dietary supplements (coenzyme Q10, glucosamine and
chondroitin sulfate, fish oil, and vitamins) were selected based on the data from the 2007 Survey and
the latest statistical commercial information [34].
3. Results
3.1. Preoperative Management for Using of Dietary Supplements
Although a preoperative assessment should address the patient’s use of dietary supplements, a 2005
study showed that 90% of anesthesiologists do not routinely ask about herbal medicine usage, and 82%
felt their knowledge of herbal medicines and their implications in patient care were inadequate [35].
Moreover, more than 70% of patients are not forthcoming about their herbal medicine use during
routine preoperative assessment [19]. In addition to prescription and over the counter medicines,
patients should be asked to bring their herbal medicines and other dietary supplements with them at the
time of the preoperative evaluation [36]. A positive history of herbal medicine use should also prompt
anesthesiologists to suspect the presence of undiagnosed disorders causing symptoms that lead to
self-medication. Patients who use herbal medicines may be more likely than those who do not to avoid
conventional diagnosis and therapy [37].
In general, the use of herbal medicines should be discontinued preoperatively. When pharmacokinetic
data for the active constituents in an herbal medication are available, the timeframe for preoperative
discontinuation can be tailored. For other herbal medicines, two weeks is recommended [38].
However, in clinical practice, because many patients require nonelective surgery, are not evaluated
until the day of surgery, or are noncompliant with instructions to discontinue herbal medications
preoperatively, they may take herbal medicines until the day of surgery. In this situation, anesthesia can
usually proceed safely at the discretion of the anesthesiologist, who should be familiar with commonly
used herbal medicines to avoid or recognize and treat complications that may arise [39,40]. For
instance, recent use of herbal medicines that inhibit platelet function (e.g., garlic, ginseng, or ginkgo)
may warrant specific strategies for procedures with substantial intraoperative blood loss (e.g., platelet
transfusion) and those that alter the risk–benefit ratio of using certain anesthetic techniques (e.g.,
neuraxial blockade) [25].
Preoperative discontinuation of all herbal medicines may not eliminate complications associated
with their use. Withdrawal of regular medications is associated with increased morbidity and mortality
after surgery. In general, medications with the potential to induce rebound and withdrawal symptoms
should be continued. The use of noncritical medications that can increase surgical risk should be
discontinued. If neither of these conditions apply, consider the patient’s risk profile and the risk of the
procedure when making perioperative management decisions [41]. In most cases, herbal medicines should
be discontinued before surgery because they are not critical. Abstinence after long-term use of an
herbal medicine such as valerian has the potential to produce acute withdrawal.
3.2. Commonly Used Herbal Medicines
3.2.1. Echinacea
Echinacea is a genus of herbaceous flowering plants in the family Asteraceae. Its nine species are
commonly called purple coneflowers. Three species, Echinacea angustifolia, Echinacea purpurea, and
Echinacea pallida, are used for prophylaxis and treatment of viral, bacterial, and fungal infections,
particularly those of upper respiratory origin, although its efficacy in the latter is doubtful [42]. A 2008
meta-analysis showed echinacea’s benefit in decreasing the incidence and duration of the common
cold [43]. Pharmacological activity cannot be attributed to a single compound, although the lipophilic
fraction, which contains alkylamides, polyacetylenes and essential oils, appears to be more active than
the hydrophilic fraction [44].
Echinacea had a number of immunostimulatory effects in early preclinical studies [45]. While there
are no studies specifically addressing interactions between echinacea and immunosuppressive drugs,
expert opinion generally warns against the concomitant use of echinacea and these drugs, owing to the
probability of diminished effectiveness [46]. In contrast to the immunostimulatory effects with
short-term use, later observations suggested that long-term use of more than eight weeks has the
potential for immunosuppression [46] and a theoretically increased risk of certain complications such
as poor wound healing and opportunistic infections. A recent phytochemical study identified a
potential immunosuppressant compound cynarin from echinacea [47]. The biological activity of
echinacea could be immunostimulatory, immunosuppressive, or anti-inflammatory depending on the
portion of the plant and extraction method [48].
Echinacea has also been associated with allergic reactions, including one reported case of
anaphylaxis [49]. Therefore, echinacea should be used with caution in patients with asthma, atopy, or
allergic rhinitis. Concerns of potential hepatotoxicity have also been raised, although documented cases
are lacking [50]. In the absence of definitive information, patients with pre-existing liver dysfunction
should be cautioned against using echinacea. Although several in vitro and in vivo pharmacokinetic
studies on echinacea have been reported, information about the pharmacokinetics of echinacea is still
limited [51]. Echinacea significantly reduced plasma concentrations of S-warfarin, but did not significantly
affect warfarin pharmacodynamics and platelet aggregation in healthy subjects [52].
3.2.2. Ephedra
Ephedra, known as ma huang in Chinese medicine, comprises the aerial parts of three principal
plant species: Ephedra sinica, Ephedra equisetina, and Ephedra intermedia var. tibetica. Ephedra
contains alkaloids including ephedrine, pseudoephedrine, norephedrine, methylephedrine, and
norpseudoephedrine [53]. In Chinese medicine, it is used to treat respiratory conditions, such as asthma
and bronchitis. Ephedra-containing dietary supplements were once widely used in the U.S. to promote
weight reduction and enhance energy. In one clinical study, the combination of caffeine and ephedra
significantly increased resting energy expenditure, heart rate and blood pressure [54]. Publicity about
adverse reactions to this herb prompted the FDA to ban its sale in 2004, but ephedra is still widely
available via the Internet.
Ephedra causes dose-dependent increases in blood pressure and heart rate. Ephedrine, the predominant
active compound, is a non-catecholamine sympathomimetic that exhibits α1, β1 and β2 activity directly
at adrenergic receptors and indirectly by releasing endogenous norepinephrine (noradrenaline). These
sympathomimetic effects have been associated with more than 800 reported adverse events, including
fatal cardiac and central nervous system complications [55].
Ephedra may affect cardiovascular function and vasoconstriction, and, in some cases, vasospasm of
coronary and cerebral arteries may cause myocardial infarction and thrombotic stroke [56]. Ephedra
also caused hypersensitivity myocarditis, characterized by cardiomyopathy with myocardial
lymphocyte and eosinophil infiltration [25]. Concomitant use of ephedra and monoamine oxidase
inhibitors can result in life-threatening hyperpyrexia, hypertension, and coma [57].
In humans, ephedrine has an elimination half-life of 5.2 h with 70%–80% of the excreted compound
remaining unchanged in the urine [58]. Based upon the pharmacokinetic data and the known cardiovascular
risks of ephedra, including myocardial infarction, stroke and cardiovascular collapse from
catecholamine depletion [57], this herb should be not used as a dietary supplement.
3.2.3. Garlic
Garlic (Allium sativum) has the potential to modify the risk of developing atherosclerosis by
reducing blood pressure, thrombus formation, and serum lipid and cholesterol levels [59]. These effects are
primarily attributed to the sulfur-containing compounds, particularly allicin and its transformation
products. Commercial garlic preparations may be standardized to a fixed alliin and allicin content [60].
Garlic inhibits platelet aggregation in vivo in a dose-dependent fashion [61,62]. The effect of one of
its constituents, ajoene, appears to be irreversible and may potentiate the effect of other platelet
inhibitors such as prostacyclin, forskolin, indomethacin, and dipyridamole [63]. Although these effects
have not been consistently demonstrated in clinical trials [64], there are several cases in the literature
on excessive dietary garlic intake or use of garlic as a medicine associated with coagulation
alterations [65]. One case report showed an interaction between garlic and warfarin, resulting in an
increased INR [66]. In addition to bleeding concerns, garlic has the potential to decrease systemic and
pulmonary vascular resistance in laboratory animals, an effect that was observed in clinical studies as
well [67].
In an early study in rats, alliin was absorbed quickly after oral administration and eliminated after
6 h. Allicin was absorbed slowly after oral administration, and its plasma peak level appeared between
0.5 h and 2 h. Even four days later, allicin could still be detected in the rats [68]. Although in one
clinical study garlic oil selectively inhibited CYP2E1 activity [69], it is still difficult to predict drug
interactions with garlic [70,71].
3.2.4. Ginger
Ginger (Zingiber officinale), a popular spice, has a long history of use in Chinese, Indian, Arabic,
and Greco-Roman herbal medicines. Ginger has a wide range of reported health benefits for those with
arthritis, rheumatism, sprains, muscular aches, pains, sore throats, cramps, constipation, indigestion,
nausea, vomiting, hypertension, dementia, fever, infectious diseases, and helminthiasis [72–74]. Ginger
contains up to 3% volatile oil, mostly monoterpenoids and sesquiterpenoids [75]. Gingerols are
representative compounds in ginger [76].
Ginger is an anti-emetic and has been used to treat motion sickness and to prevent nausea after
laparoscopy [77]. In an in vitro study, gingerols and related analogues inhibited arachidonic
acid-induced human platelet serotonin release and aggregation, with a potency similar to that of
aspirin [76]. In another in vitro study, the antiplatelet effects of 20 ginger constituents were evaluated.
Five constituents showed antiplatelet activities at relatively low concentrations. One of the ginger
compounds (8-paradol) was the most potent COX-1 inhibitor and antiplatelet aggregation agent [78].
In a case report, a ginger-phenprocoumon combination resulted in an elevated INR and epistaxis [79].
Although the sample size was relatively small, the platelet inhibition potential of ginger has been
supported in a pilot clinical study [80].
3.2.5. Ginkgo
Ginkgo is derived from the leaf of Ginkgo biloba, the sole surviving species of the large plant
division Ginkgophyta, once widespread throughout the world 180 million years ago. Ginkgo extracts
used as medicine contain terpene trilactones, flavonoids, biflavones, proanthocyanidins, alkylphenols,
and polyprenols [81,82]. Ginkgo has been used for cognitive disorders, peripheral vascular disease,
age-related macular degeneration, vertigo, tinnitus, erectile dysfunction, and altitude sickness [83–85].
Studies have suggested that ginkgo may stabilize or improve cognitive performance in patients with
Alzheimer’s disease and multi-infarct dementia [86] but not in healthy geriatric patients [87]. When
plasma and brain levels of terpene trilactones were evaluated in vivo, ginkgolides A and B and
bilobalide crossed the blood-brain barrier after a single oral dose of ginkgo extract [88]. Because the
compounds believed to be responsible for its pharmacological effects are the terpene trilactones and
flavonoids, most commercial ginkgo extracts are standardized for their content of these
compounds [81].
Ginkgo appears to alter vasoregulation, act as an antioxidant, modulate neurotransmitter and
receptor activity and inhibit platelet-activating factor (PAF). Of these effects, the inhibition of PAF
raises the greatest concern for surgical patients [38]. Ginkgo showed antiplatelet and antithrombotic
effects in in vivo animal models [89,90]. In a clinical trial, ginkgo reduced platelet aggregation but had
no effect on coagulation assays or bleeding time [91]. In a study of 50 healthy male volunteers, 29
received 2 × 120 mg/day of ginkgo extract for seven days; however, none in the ginkgo group had
abnormal platelet and coagulation parameters [92]. Despite lack of evidence from a clinical trial, ten
case reports have implicated ginkgo as a cause of catastrophic bleeding [93,94], including one
case of spontaneous hyphema [95], one case of postoperative bleeding after laparoscopic
cholecystectomy [96], and one of cerebral bleeding without structural abnormalities in the patient [94].
Terpene trilactones are highly bioavailable when administered orally. The elimination half-lives of
the terpene trilactones after oral administration are between 3 h and 10 h. For ginkgolide B, a dosage
of 40 mg twice daily resulted in a higher area under the curve, and a longer half-life and residence time
than after a single 80 mg dose. A once daily dose of 80 mg guaranteed a higher maximum
concentration peak (Tmax). Tmax was reached 2–3 h after administration with both dosages [97].
3.2.6. Ginseng
Among the several species of ginseng used for their pharmacological effects, Asian ginseng (Panax
ginseng) and American ginseng (Panax quinquefolius) are the most commonly described [17,98].
Ginseng has been labeled an “adaptogen” since it reportedly protects the body against stress and
restores homeostasis [99–101]. Because its pharmacological actions are attributed to the ginsenosides,
a group of steroidal saponin compounds, many commercially available ginseng preparations have been
standardized to ginsenoside content [17,102].
The many heterogeneous and sometimes opposing effects of different ginsenosides [103,104] give
ginseng a broad but incompletely understood pharmacological profile with regards to its effects on
general health, fatigue, immune function, cancer, cardiovascular disease, diabetes mellitus, cognitive
function, viral infections, sexual function, and athletic performance [99]. The underlying mechanism
appears to be similar to that classically described for steroid hormones. A potential therapeutic use for
this herb lies in its ability to lower postprandial blood glucose in both type 2 diabetics and
non-diabetics [105,106], an effect that may create unintended hypoglycemia in patients who have
fasted before surgery. In a recent case report, after the oral administration a large amount of ginseng, a
female patient with no cardiovascular risk factors developed prolonged QT with subsequent Torsades
de pointes, suggesting that a high dose of ginseng may have a risk of inducing arrhythmia [107].
There is concern about ginseng’s effect on hemostasis. One early study suggested that the
antiplatelet activity of panaxynol, a constituent of ginseng, may be irreversible in humans [108]. Other
studies found that ginseng extract and ginsenosides inhibit platelet aggregation in vitro [109,110],
and prolong both thrombin time and activated partial thromboplastin time in in vivo animal
models [111,112]. The clinical evidence implicating ginseng as a cause of bleeding is weak and based
on only a few case reports [93]. Although ginseng may inhibit the coagulation cascade, in one case its
use was associated with a significant decrease in warfarin anticoagulation [113]. Subsequently, a
study involving volunteers showed that American ginseng interfered with warfarin-induced
anticoagulation [114]. In another clinical trial, warfarin’s apparent clearance was moderately increased
with Asian ginseng [115]. Because warfarin is often used after orthopedic or vascular procedures, this
drug interaction may affect the outcome of the procedure.
In rats, after an intravenous infusion of ginseng, ginsenosides Re and Rg1 were eliminated quickly
from the body with a T1/2 between 0.7 h and 4 h; ginsenosides Rb1 and Rd were eliminated slowly
from the body with a T1/2 between 19 h and 22 h [116]. After the oral administration of ginseng,
ginsenoside Rb1 reached the maximum plasma concentration at approximately 4 h with a prolonged
half-life [117,118].
3.2.7. Green Tea
Tea from Camellia sinensis is one of the most ancient drinks and the second most widely consumed
beverage in the world [119,120]. Tea can be classified into three types: green, oolong, and black.
Green tea, which is non-fermented and derived directly from drying and steaming fresh tea leaves,
contains polyphenolic compounds. The catechins in green tea account for 16%–30% of its dry weight.
Epigallocatechin-3-gallate (EGCG), the most predominant catechin in green tea, is responsible for
much of the biological activity mediated by green tea [120].
In an early in vitro and in vivo study, both green tea and EGCG significantly prolonged mouse
tail bleeding time in conscious mice. They inhibited adenosine diphosphate- and collagen-induced rat
platelet aggregation in a dose-dependent manner [121]. The antiplatelet activity may result from the
inhibition of thromboxane A2 formation. Because ATP release from a dense granule is inhibited by
catechins in washed platelets, thromboxane A2 formation may have been inhibited by preventing
arachidonic acid liberation and thromboxane A2 synthase [122,123]. Regarding a possible adverse
effect of green tea on platelets, one case report showed that after a patient consumed a weight-loss
product containing green tea, thrombotic thrombocytopenic purpura developed [124]. Since green tea
contains vitamin K, drinking green tea may antagonize the anticoagulant effects of warfarin [125].
In a randomized, double-blind, placebo-controlled study, eight subjects received oral EGCG in a

single dose of 50–1600 mg. In each dosage group, the kinetic profile revealed rapid absorption with a
one-peak plasma concentration versus time course, followed by a multiphasic decrease consisting of a
distribution phase and an elimination phase. The mean half-life values observed were between 1.9 h
and 4.6 h [126]. In another pilot clinical study, after five healthy subjects took tea extract orally, the
concentration of EGCG in plasma was determined; the half-life of EGCG was between 2.2 h and
3.4 h [127].
3.2.8. Kava
Kava is derived from the dried root of the pepper plant Piper methysticum. Kava has gained
popularity as an anxiolytic and sedative, and kavalactones appear to be the source of kava’s
pharmacological activity [53].
Kava possesses psychomotor activities. The kavalactones have dose-dependent effects on the
central nervous system including antiepileptic, neuroprotective, and local anesthetic properties [128,129].
Kava may act as a sedative or hypnotic by potentiating inhibitory neurotransmission of
γ-aminobutyric acid (GABA) [130]. The kavalactones increased barbiturate sleep time in laboratory
animals [131]. This effect may explain the mechanism underlying the report of a coma attributed to an
alprazolam–kava interaction [132]. Although kava has abuse potential, whether long-term use can
result in addiction, tolerance, and acute withdrawal after abstinence has not been satisfactorily
investigated. Continuous kava use may elevate gamma glutamyl transpeptidase (GGT) levels, raising
concerns about hepatotoxicity [133]. In addition, the hepatotoxicity of kava may be associated with the
inappropriate use of plant products and processes [134]. With continuous use, kava produces “kava
dermopathy”, characterized by reversible scaly cutaneous eruptions [135].
In an in vitro investigation, a kava compound (+)-kavain suppressed the aggregation of human
platelets [136]. A pilot survey of extensive usage of kava showed that kava users were more likely to
complain of poor health and had increased red-cell volume and decreased platelet volume [137]. Kava
inhibits cyclooxygenase to potentially decrease renal blood flow and interfere with platelet
aggregation. Consumption of kava has potential cardiovascular effects that could manifest and the
elimination half-life of kavalactones is 9 h [138]. The kavalactone compound kawain was well
absorbed after oral administration during surgery [139]. In spite of safety concerns, including previous
reports of liver toxicity associated with kava products in humans [140,141], kava is still available in
the United States.
Peak plasma levels occur 1.8 h after an oral dose, and >90% of the dose and its metabolites were
eliminated within 72 h [142].
3.2.9. Saw Palmetto
Saw palmetto (Serenoa repens) is a dwarf palm tree native to Florida and other parts of the
southeastern USA. The dried ripe berry extract of saw palmetto is used by men in the United States to
treat symptoms associated with benign prostatic hypertrophy (BPH) [143]. The major constituents of
saw palmetto are fatty acids and their glycerides (i.e., triacylglycerides and monoacylglycerides),
carbohydrates, steroids, flavonoids, resin, pigment, tannin, and volatile oil. The pharmacological
activity of saw palmetto has not been attributed to a single compound [53].
The mechanisms of saw palmetto, including antiandrogenic, anti-inflammatory, and antiproliferative
effects mediated through the inhibition of growth factors, have been studied in vitro [144]. An in vivo
study revealed that at a clinically relevant dose, saw palmetto exerts a direct effect on the pharmacological
receptors in the lower urinary tract, thereby improving urinary dysfunction in patients with BPH and
overactive bladders [145]. The potential of saw palmetto for relieving BPH symptoms could be
achieved by multiple synergistic mechanisms.
Platelet function was not affected by the administration of saw palmetto in a clinical study [93], and
two case reports provided little evidence to implicate saw palmetto as a cause of bleeding. In a patient
undergoing a craniotomy, however, saw palmetto was associated with excessive surgical bleeding that
required termination of the procedure. This complication was attributed to saw palmetto’s
anti-inflammatory effects, specifically the inhibition of cyclooxygenase and subsequent platelet
dysfunction [146]. Another case of hematuria and coagulopathy in a patient who used saw palmetto
was reported [147].
3.2.10. St John’s Wort
St John’s wort is the common name for Hypericum perforatum, primarily used as an antidepressant.
The popularity of St John’s wort is reflected in the large number of clinical trials, meta-analyses and
reviews of its effectiveness as an antidepressant. The herb is more effective than a placebo in the
treatment of mild to moderate depression and the incidence of side effects is low. In the treatment of
major depression, however, St John’s wort is less effective [148]. The compounds believed to be
responsible for pharmacological activity are hypericin and hyperforin [149]; thus, commercial
preparations are often standardized for the content of the two compounds [150].
St John’s wort inhibits serotonin, norepinephrine and dopamine reuptake [151]. Concomitant use
of this herb with or without serotonin reuptake inhibitors may create a syndrome of central serotonin
excess [152]. Although in vitro data implicated monoamine oxidase inhibition as a possible
mechanism of action, a number of later investigations have demonstrated that monoamine oxidase
inhibition with St John’s wort is insignificant in vivo [153].
The use of St John’s wort can significantly increase the metabolism of many other drugs [70,154].
For example, it induces the cytochrome P450 3A4 isoform, approximately doubling its metabolic
activity [155,156]. Interactions with substrates of the 3A4 isoform including indinavir sulfate [157],
ethinylestradiol [158], and cyclosporine have been documented. In two case reports of heart transplant
patients, after taking St John’s wort, their plasma cyclosporine concentrations became subtherapeutic
and acute transplant rejection was shown. After stopping St John’s wort, plasma cyclosporine
remained within the therapeutic range with no further episodes of rejection [159]. In one series of 45 organ
transplant patients, St John’s wort was associated with an average decrease of 49% of cyclosporine
levels in blood [160]. Another group reported two cases of acute heart transplant rejection associated
with this particular pharmacokinetic interaction [159]. Other P450 3A4 substrates are alfentanil,
midazolam, lidocaine, calcium channel blockers and 5-hydroxytryptamine receptor antagonists.
In addition to the 3A4 isoform, the cytochrome P450 2C9 isoform also may be induced.
The anticoagulant effect of warfarin, a substrate of the 2C9 isoform, was reduced in seven reported
cases [158]. Other 2C9 substrates include the non-steroidal anti-inflammatory drugs. Furthermore,
enzyme induction by St John’s wort may be more pronounced when other herbal enzyme inducers are
taken concomitantly. St John’s wort also affects digoxin pharmacokinetics [161]. In rats, St John’s wort
markedly altered hepatocyte intracellular accumulation of irinotecan and its major metabolite (SN-38)
and the glucuronidation of SN-38 [162].
Two clinical trials showed that St John’s wort increased estrogen metabolism and caused breakthrough
menstrual bleeding in users of estrogen-based oral contraceptives [163,164]. In one case report,
St John’s wort may have caused severe unilateral epistaxis requiring surgical arrest of bleeding via
endoscopic sphenopalatine artery ligation and anterior ethmoidal artery ligation [165].
Several clinical evaluations of the single-dose and steady-state pharmacokinetics of hypericin and
hyperforin have been conducted in humans [166]. After oral administration, peak plasma levels of
hypericin and hyperforin were obtained between 2.5–8.1 h and 2.5–4.4 h, respectively, and their
median elimination half-lives were 6.0–48.2 h and 8.5–19.6 h, respectively.
3.2.11. Valerian
Valerian, which consists of the root of Valeriana officinalis and a number of other Valeriana
species, is an herb native to the temperate areas of the Americas, Europe, and Asia [53]. It is used as a
sedative, particularly in the treatment of insomnia, and virtually all herbal sleep-aids contain
valerian [167]. The compounds in valerian act synergistically, but the sesquiterpenes are the primary
source of valerian’s pharmacological effects. Commercially available preparations may be
standardized to valerenic acid [168].
Valerian produces dose-dependent sedation and hypnosis [169]. These effects appear to be mediated
through the modulation of GABA neurotransmission and receptor function [170]. Valerian increased
barbiturate sleep time in experimental animals [171]. In several randomized, placebo-controlled trials
in humans, there is a mild subjective improvement in sleep with valerian, especially when used for
two weeks or more [172,173]. Objective tests have had less consistent results with little or no
improvement in sleep noted [174]. In one patient, valerian withdrawal appeared to mimic an acute
benzodiazepine withdrawal syndrome characterized by delirium and cardiac complications after
surgery. Symptoms were attenuated by benzodiazepine administration [175]. Based upon these
findings, valerian is expected to potentiate the sedative effects, like midazolam, via the GABA
receptor.
The pharmacokinetics of valerian were evaluated in two clinical studies. In five healthy adults,
serum concentration of valerenic acid was at maximum between 1 and 2 h after administration.
Valerenic acid was measurable in serum for at least 5 h after the valerian dose [176]. In another study,
plasma peak levels appeared between 0.47 h and 1.7 h. The large variability in the pharmacokinetics of
valerenic acid may contribute to the inconsistencies in its effect as a sleep aid [177].
Most of the published clinical trials do not record side effects of valerian. In a trial involving 61
patients, there were only three cases of side-effects: two of headache and one of morning hang-over [169].
Another possible rare adverse effect of valerian is hepatotoxicity, found in one case report [178].
Abrupt discontinuation in patients who may be physically dependent on valerian risk benzodiazepine-
like withdrawal. Based upon the mechanism of action and a reported case of efficacy [175],
benzodiazepines can be used to treat valerian withdrawal symptoms.
3.2.12. Other Herbal Medicines
In the survey conducted in 2007, the top ten herbal medicines also included soy isoflavones, grape
seed extract, and milk thistle. There is no report on adverse effects related to coagulation and platelet
function for these herbs. Antiplatelet aggregation activity and herb–drug interactions, however, were
found in other herbs including boldo (Peumus boldus), Danshen (Salvia miltiorrhiza), Dong quai
(Angelica sinensis) and papaya (Carica papaya) [179].
Danshen is a very commonly used Chinese herbal medicine for cardiovascular conditions [180–182]. In
a clinical trial, this herbal medicine has been shown to be effective in reducing skin flap ischemia and
necrosis after mastectomy [183]. The effects of antiplatelet aggregation of Danshen have been reported
from a number of investigations. An in vitro study demonstrated that the intracellular signaling
pathway involved in the antiplatelet action of tanshinone IIA could modulate tubulin acetylation and
inhibit Erk-2 phosphorylation [184,185]. Cryptotanshinone is another pharmacologically active
compound identified from Danshen. In a very recent study, Maione et al. reported that
cryptotanshinone inhibited rat platelet aggregation and endowed of Gi-coupled P2Y12 receptor
antagonist [186].
3.3. Other Commonly Used Dietary Supplements
3.3.1. Coenzyme Q10
Coenzyme Q10 (CoQ10), or ubidecarenone, is a single-constituent antioxidant compound structurally

related to vitamin K. Endogenous CoQ10 may prevent the membrane transition pore from opening, as it
counteracts several apoptotic events, such as DNA fragmentation, cytochrome c release, and
membrane potential depolarization [53].
The interaction between CoQ10 and warfarin was investigated in rats [187]. Following the oral
administration of 1.5 mg/kg of racemic warfarin to rats during an eight-day oral regimen of CoQ10
(10 mg/kg daily), no apparent effect was observed on the serum protein binding of warfarin
enantiomers. Treatment with CoQ10 did not affect the absorption and distribution of the S- and
R-enantiomers of warfarin but increased total serum clearance of both R- and S-warfarin. The increased
clearance values could be attributed to the acceleration of certain metabolic pathways and renal
excretion of the warfarin enantiomers.
An in vitro study using human liver microsomes led to a relatively accurate pharmacokinetic
prediction of CoQ10 activity. A 32% and 17% increase in the total clearance of S- and R-warfarin, was
predicted with the coadministration of 100 mg CoQ10 [188]. CoQ10 may decrease the effects of
warfarin [189], but results were inconsistent in another controlled, clinical trial [190]. In 171 patients,
coadministration of CoQ10 with warfarin appeared to increase the risk of bleeding [191]. Clinical
pharmacokinetic study suggested that CoQ10 had a prolonged elimination half-life (38–92 h) after oral
administration [192].
3.3.2. Glucosamine and Chondroitin Sulfate
Osteoarthritis (OA), a chronic illness and the most common of all the joint diseases, affects about
15% of the world’s population and is three times more common in women than in men [193]. Standard
therapies can alleviate the symptoms of OA to some extent but cannot prevent disease progression.
A number of alternative substances have been touted as beneficial for OA. Although their mode of
action may be complex, glucosamine and chondroitin sulfate have been widely accepted as
supplements in the management of OA because they are the essential components of proteoglycan in
normal cartilage [194]. When a large-scale trial evaluated glucosamine and chondroitin sulfate alone
or in combination, pain was not reduced in a group of patients with OA of the knee. Exploratory
analyses suggested that the two in combination might be effective in a subgroup of patients with
moderate-to-severe knee pain [195].
Long-term clinical data regarding the safety of glucosamine and chondroitin sulfate alone, or
in combination, are limited. The use of chondroitin sulfate alone is well tolerated and without any
significant adverse drug interaction [194]. One concern regarding the use of glucosamine is its
potential to cause or worsen diabetes in animal models [196], an effect supported by clinical
studies [197]. In a published report from the FDA MedWatch database, there were 20 reports of
glucosamine or glucosamine-chondroitin sulfate use with warfarin. Coagulation was altered as
manifested by increased INR or increased bleeding or bruising [198].
When glucosamine is taken orally, 90% of it is absorbed. Because of extensive first-pass
metabolism, only 25% bioavailability is achieved by oral administration compared with a bioactivity
of 96% with intravenous administration [199]. Peak plasma levels occurred 4 h after an oral dose and
declined to baseline after about 48 h [200]. Chondroitin sulfate was absorbed slowly after oral
ingestion with a plasma peak at 8.7 h and a decline to baseline at about 24 h [201].
3.3.3. Fish Oil
The intake of fish oil supplements containing omega-3 fatty acids (EPA and DHA) reduces the
incidence of many chronic diseases that involve inflammatory processes including cardiovascular
diseases, inflammatory bowel disease, cancer, rheumatoid arthritis, and neurodegenerative illnesses [202].
In a recent study, however, omega-3 did not reduce the rate of death in patients with cardiovascular
risk factors [203].
Omega-3 fatty acids, however, may inhibit platelet aggregation and increase the risk of bleeding. In
vitro experiments have demonstrated an anti-platelet aggregatory effect of omega-3 fatty acids [204],
and inhibition correlated with platelet cAMP levels [205]. In vivo studies show that omega-3 fatty
acids decreased platelet aggregation but did not influence bleeding time [206,207]. In a clinical study,
the inhibition of platelet aggregation by omega-3 fatty acid was gender-specific. EPA was significantly
effective in reducing platelet aggregation in males, whereas DHA was not effective compared to the
placebo. In females, DHA significantly reduced platelet aggregation but EPA did not [208].
Although evidence for significant bleeding concerns was not found in clinical trials [209,210],
several case reports have illustrated a possible interaction between warfarin and omega-3 fatty
acids [211]. Extremely elevated INR associated with warfarin in combination with omega-3 fatty acids
was found in two cases [212,213]. In another case, after a minor fall, a patient developed a subdural
hematoma requiring a craniotomy that likely was precipitated by concomitant use of high-dose
omega-3 fatty acids with both aspirin and warfarin [214].
3.3.4. Vitamins
Vitamins are organic compounds needed for normal metabolic functions. They are traditionally
categorized as fat-soluble (vitamins A, D, E, and K) or water-soluble (vitamins B and C and biotin).
Only vitamins C and E will be discussed here because of their potential effects related to coagulation
and platelet function.
Vitamin C is a micronutrient essential for human health. Because humans cannot synthesize it,
human survival depends on obtaining vitamin C from foods. The recommended dietary allowance
(RDA) of vitamin C is 60 mg daily. The tolerable upper intake level is 2000 mg/day according to the
Institute of Medicine [215]. The toxic effects of vitamin C are few and dose-dependent. Doses of
vitamin C greater than 2000 mg/day have been associated with multiple adverse effects. Ingestion of 3
to 5 g at once may cause diarrhea and bloating [53]. Large doses may also precipitate hemolysis in
patients with glucose 6-phosphate dehydrogenase deficiency [216]. One case report suggested that
vitamin C might interfere with the action of warfarin [217], but other clinical studies did not support
the theory [218,219].
Vitamin E is a potent lipid-soluble antioxidant in human plasma and tissues. It has many forms and
biological activities. The most active form is α-tocopherol. The Food and Nutrition Board defined the
human requirements for vitamin E as only α-tocopherol, specifically those forms with 2R-α-tocopherol
stereochemistry [220]. The RDA for vitamin E is 15 mg/day (or 22.4 IU) [53], which can be met by
dietary sources. The essential upper limit for safety is 1000 mg/day, but some experts advise avoiding
supplementation with doses higher than 400 mg/day [221]. Vitamin E intakes are associated with
an increased tendency to bleed and in vitro and in vivo studies showed that vitamin E inhibits platelet
aggregation. A vitamin E quinone metabolite may be responsible for the effects of vitamin E [222],
and the reduced platelet adhesiveness of vitamin E probably accompanies incorporation by plasma
lipoproteins [223]. Risk of bleeding increased when vitamin E and warfarin were combined in an
in vitro study [224]; however, this interaction was not supported by a preliminary clinical study [225].
Moderate doses of vitamin E (400 IU daily) increased the risk of bleeding because of inhibition of
platelet aggregation and antagonism of vitamin K-dependent clotting factors [226]. In one clinical
study, platelet adhesion decreased significantly in volunteers who took 400 IU of vitamin E plus
325 mg/day aspirin, compared to volunteers who took 325 mg/day of aspirin alone [227]. Data from
another trial were unable to reproduce these results [228].
Other top ten dietary supplements include flaxseed oil, fiber or psyllium, cranberry, melatonin,
methysulfonylmethane (MSM) and lutein [33]. No special concerns have been published associated
with bleeding risk or other platelet function changes from the use of these supplements.
4. Discussion
Although there are no official standards or guidelines on the preoperative use of alternative
medicine, public and professional educational information advises that natural products be
discontinued at least 2–3 weeks before surgery [38,229]. However, in practice, evaluating patients
2–3 weeks before elective surgery may not be practical. Moreover, some patients require non-elective
surgery or are non-compliant with instructions to discontinue herbal medications preoperatively. These
factors and the extensive use of herbal medicines may mean that herbal medications are taken until the
time of surgery. Pharmacokinetic data on selected active constituents indicate that some herbal
medications are eliminated quickly and may be discontinued close to the time of surgery.
The administration of warfarin in the perioperative period may be complicated by the potential
drug–supplement interactions described above. Because the effects of dietary supplements on
coagulation and platelet function are not well characterized and their effects are difficult to predict, it is
prudent to advise their discontinuation before surgery [230].
Data on the safety of dietary supplements in the perioperative period are limited. Since patients
often self-medicate with supplements without disclosure to their health care providers, physicians
should ask patients about their present or past use of dietary supplements. A limitation of this review is
that currently available data are mostly based on in vivo and limited clinical studies or case reports,
whereas controlled clinical trials for natural products on coagulation and platelet function are largely
unavailable. Nevertheless, we summarized potential perioperative effects of commonly used natural
products. Data in this article can help physicians avoid potential problems associated with the use of
natural products during the perioperative period.
5. Conclusions
Natural products are gaining popularity in the United States. There is extensive literature on the
beneficial and adverse effects of natural products; however, safety data related to their bleeding risks
are limited. To understand these potential complications of natural products, clinicians should
explicitly elicit and document a history of natural product use by patients. In this article, we reviewed
possible effects of natural products on coagulation and platelet function. Pharmacodynamic and
pharmacokinetic information of commonly used herbal medicine and dietary supplements, and their
interactions with anticoagulant medications were discussed. It is important for physicians and health
care professionals to stay informed about commonly used natural products and their potential adverse
effects, including those on coagulation and platelet function.
Acknowledgments
This work was supported in part by NIH/NCCAM grants AT004418, and AT005362.
Author Contributions
C.Z.W.: conception and design, data acquisition and interpretation of data, drafting and finalizing
the manuscript; J.M.: conception and design, data interpretation, and manuscript revision; and
C.S.Y.: conception and design, data interpretation, and manuscript revision.
Conflicts of Interest
The authors declare that they have no competing interests.

Abbreviations
CAM: Complementary and Alternative Medicine; OA: Osteoarthritis; EPA: Eicosapentaenoic Acid;
DHA: Docosahexaenoic Acid; RDA: Recommended Dietary Allowance; and
MSM: Methysulfonylmethane.
References
1. Shekelle, P.G.; Morton, S.C.; Suttorp, M.J.; Buscemi, N.; Friesen, C. Challenges in systematic
reviews of complementary and alternative medicine topics. Ann. Intern. Med. 2005, 142, 1042–1047.
2. Miller, F.G.; Emanuel, E.J.; Rosenstein, D.L.; Straus, S.E. Ethical issues concerning research in
complementary and alternative medicine. JAMA 2004, 291, 599–604.
3. Bega, D.; Gonzalez-Latapi, P.; Zadikoff, C.; Simuni, T. A review of the clinical evidence for
complementary and alternative therapies in Parkinson’s disease. Curr. Treat. Opt. Neurol. 2014,
16, 314.
4. Grant, S.J.; Yu, S.B.; Kiat, H.; Chang, D. The use of complementary and alternative medicine by
people with cardiovascular disease: A systematic review. BMC Public Health 2012, 12, 299.
5. Medagama, A.B.; Bandara, R. The use of complementary and alternative medicines (CAMs) in
the treatment of diabetes mellitus: Is continued use safe and effective? Nutr. J. 2014, 13, 102.
6. Fouladbakhsh, J. Complementary and alternative modalities to relieve osteoarthritis symptoms:
A review of the evidence on several therapies often used for osteoarthritis management. Orthop. Nurs.
2012, 31, 115–121.
7. Yamaguchi, Y.; Miyahara, E.; Hihara, J. Efficacy and safety of orally administered Lentinula
edodes mycelia extract for patients undergoing cancer chemotherapy: A pilot study. Am. J. Chin.
Med. 2011, 39, 451–459.
8. Geller, S.E.; Studee, L. Botanical and dietary supplements for mood and anxiety in menopausal
women. Menopause 2007, 14, 541–549.
9. Wang, J.; Li, Y.; Ni, C.; Zhang, H.; Li, L.; Wang, Q. Cognition research and constitutional
classification in Chinese medicine. Am. J. Chin. Med. 2011, 39, 651–660.
10. Reddy, K.K.; Grossman, L.; Rogers, G.S. Common complementary and alternative therapies
with potential use in dermatologic surgery: Risks and benefits. J. Am. Acad. Dermatol. 2011, 68,
e127–e135.
11. Chan, P.C.; Peckham, J.C.; Malarkey, D.E.; Kissling, G.E.; Travlos, G.S.; Fu, P.P. Two-year
toxicity and carcinogenicity studies of Panax ginseng in Fischer 344 rats and B6C3F1 mice.
Am. J. Chin. Med. 2011, 39, 779–788.
12. Efferth, T.; Koch, E. Complex interactions between phytochemicals. The multi-target therapeutic
concept of phytotherapy. Curr. Drug Targets 2011, 12, 122–132.
13. Rodriguez, M.; Du, G.J.; Wang, C.Z.; Yuan, C.S. Letter to the editor: Panaxadiol’s anticancer
activity is enhanced by epicatechin. Am. J. Chin. Med. 2010, 38, 1233–1235.
14. Cohen, M.H.; Eisenberg, D.M. Potential physician malpractice liability associated with
complementary and integrative medical therapies. Ann. Intern. Med. 2002, 136, 596–603.
15. Ashar, B.H.; Rice, T.N.; Sisson, S.D. Physicians’ understanding of the regulation of dietary
supplements. Arch. Intern. Med. 2007, 167, 966–969.
16. Wang, C.Z.; Mehendale, S.R.; Calway, T.; Yuan, C.S. Botanical flavonoids on coronary heart
disease. Am. J. Chin. Med. 2011, 39, 661–671.
17. Qi, L.W.; Wang, C.Z.; Yuan, C.S. Isolation and analysis of ginseng: Advances and challenges.
Nat. Prod. Rep. 2011, 28, 467–495.
18. Tsen, L.C.; Segal, S.; Pothier, M.; Bader, A.M. Alternative medicine use in presurgical patients.
Anesthesiology 2000, 93, 148–151.
19. Kaye, A.D.; Clarke, R.C.; Sabar, R.; Vig, S.; Dhawan, K.P.; Hofbauer, R.; Kaye, A.M. Herbal
medicines: Current trends in anesthesiology practice—A hospital survey. J. Clin. Anesth. 2000,
12, 468–471.
20. King, A.R.; Russett, F.S.; Generali, J.A.; Grauer, D.W. Evaluation and implications of natural
product use in preoperative patients: A retrospective review. BMC Complement. Altern. Med.
2009, 9, 38.
21. Childress, L.; Gay, A.; Zargar, A.; Ito, M.K. Review of red yeast rice content and current Food
and Drug Administration oversight. J. Clin. Lipidol. 2013, 7, 117–122.
22. Bhalerao, S.; Deshpande, T.; Thatte, U. Prakriti (Ayurvedic concept of constitution) and
variations in platelet aggregation. BMC Complement. Altern. Med. 2012, 12, 248.
23. Lee, J.J.; Kim, T.; Cho, W.K.; Ma, J.Y. Antithrombotic and antiplatelet activities of Soshiho-tang
extract. BMC Complement. Altern. Med. 2013, 13, 137.
24. Choi, J.H.; Kim, D.W.; Park, S.E.; Choi, B.S.; Sapkota, K.; Kim, S.; Kim, S.J. Novel
thrombolytic protease from edible and medicinal plant Aster yomena (Kitam.) Honda with
anticoagulant activity: Purification and partial characterization. J. Biosci. Bioeng. 2014, 118,
372–377.
25. Ang-Lee, M.K.; Moss, J.; Yuan, C.S. Herbal medicines and perioperative care. JAMA 2001, 286,
208–216.
26. Wang, C.Z.; Calway, T.; Yuan, C.S. Herbal medicines as adjuvants for cancer therapeutics. Am. J.
Chin. Med. 2012, 40, 657–669.
27. Butterweck, V.; Derendorf, H. Potential of pharmacokinetic profiling for detecting herbal
interactions with drugs. Clin. Pharmacokinet. 2008, 47, 383–397.
28. Wang, Y.; Xie, H.; Pan, S.L. Pharmacokinetics of laetispicine and its brain distribution in rats.
Am. J. Chin. Med. 2010, 38, 895–907.
29. Shaw, D. Toxicological risks of Chinese herbs. Planta Med. 2010, 76, 2012–2018.
30. Dog, T.L.; Marles, R.; Mahady, G.; Gardiner, P.; Ko, R.; Barnes, J.; Chavez, M.L.; Griffiths, J.;
Giancaspro, G.; Sarma, N.D. Assessing safety of herbal products for menopausal complaints:
An international perspective. Maturitas 2010, 66, 355–362.
31. Cordier, W.; Steenkamp, V. Herbal remedies affecting coagulation: A review. Pharm. Biol. 2012,
50, 443–452.
32. Barnes, P.M.; Powell-Griner, E.; McFann, K.; Nahin, R.L. Complementary and alternative
medicine use among adults: United States, 2002. Adv. Data 2004, 343, 1–19.
33. Barnes, P.M.; Bloom, B.; Nahin, R.L. Complementary and alternative medicine use among adults
and children: United States, 2007. Natl. Health Stat. Rep. 2008, 12, 1–23.
34. Blumenthal, M.; Lindstrom, A.; Lynch, M.E.; Rea, P. Herb sales continue growth—Up 3.3% in
2010. HerbalGram 2010, 90, 64–67.
35. McKenzie, A.G.; Simpson, K.R. Current management of patients taking herbal medicines:
A survey of anaesthetic practice in the UK. Eur. J. Anaesthesiol. 2005, 22, 597–602.
36. Skinner, C.M.; Rangasami, J. Preoperative use of herbal medicines: A patient survey. Br. J.
Anaesth. 2002, 89, 792–795.
37. Cirigliano, M.; Sun, A. Advising patients about herbal therapies. JAMA 1998, 280, 1565–1566.
38. Rowe, D.J.; Baker, A.C. Perioperative risks and benefits of herbal supplements in aesthetic
surgery. Aesthet. Surg. J. 2009, 29, 150–157.
39. Stohs, S.J.; Dudrick, S.J. Nutritional supplements in the surgical patient. Surg. Clin. North Am.
2011, 91, 933–944.
40. Moss, J.; Yuan, C.S. Herbal medicines and perioperative care. Anesthesiology 2006, 105, 441–442.
41. Whinney, C. Perioperative medication management: General principles and practical applications.
Cleve. Clin. J. Med. 2009, 76 (Suppl. 4), S126–S132.
42. Turner, R.B.; Bauer, R.; Woelkart, K.; Hulsey, T.C.; Gangemi, J.D. An evaluation of Echinacea
angustifolia in experimental rhinovirus infections. N. Engl. J. Med. 2005, 353, 341–348.
43. Shah, S.A.; Sander, S.; White, C.M.; Rinaldi, M.; Coleman, C.I. Evaluation of echinacea for
the prevention and treatment of the common cold: A meta-analysis. Lancet Infect. Dis. 2007, 7,
473–480.
44. Barnes, J.; Anderson, L.A.; Gibbons, S.; Phillipson, J.D. Echinacea species (Echinacea
angustifolia (DC.) Hell., Echinacea pallida (Nutt.) Nutt., Echinacea purpurea (L.) Moench): A
review of their chemistry, pharmacology and clinical properties. J. Pharm. Pharmacol. 2005, 57,
929–954.
45. Lee, A.N.; Werth, V.P. Activation of autoimmunity following use of immunostimulatory herbal
supplements. Arch. Dermatol. 2004, 140, 723–727.
46. Boullata, J.I.; Nace, A.M. Safety issues with herbal medicine. Pharmacotherapy 2000, 20,
257–269.
47. Dong, G.C.; Chuang, P.H.; Chang, K.C.; Jan, P.S.; Hwang, P.I.; Wu, H.B.; Yi, M.; Zhou, H.X.;
Chen, H.M. Blocking effect of an immuno-suppressive agent, cynarin, on CD28 of T-cell
receptor. Pharm. Res. 2009, 26, 375–381.
48. Benson, J.M.; Pokorny, A.J.; Rhule, A.; Wenner, C.A.; Kandhi, V.; Cech, N.B.; Shepherd, D.M.
Echinacea purpurea extracts modulate murine dendritic cell fate and function. Food Chem.
Toxicol. 2010, 48, 1170–1177.
49. Mullins, R.J. Echinacea-associated anaphylaxis. Med. J. Aust. 1998, 168, 170–171.
50. Huntley, A.L.; Thompson Coon, J.; Ernst, E. The safety of herbal medicinal products derived
from Echinacea species: A systematic review. Drug Saf. 2005, 28, 387–400.
51. Toselli, F.; Matthias, A.; Gillam, E.M. Echinacea metabolism and drug interactions: The case for
standardization of a complementary medicine. Life Sci. 2009, 85, 97–106.
52. Abdul, M.I.; Jiang, X.; Williams, K.M.; Day, R.O.; Roufogalis, B.D.; Liauw, W.S.; Xu, H.;
Matthias, A.; Lehmann, R.P.; McLachlan, A.J. Pharmacokinetic and pharmacodynamic
interactions of echinacea and policosanol with warfarin in healthy subjects. Br. J. Clin.
Pharmacol. 2010, 69, 508–515.
53. Coates, P.M.; Betz, J.M.; Blackman, M.R.; Cragg, G.M.; Levine, M.; Moss, J.; White, J.D.,
Encyclopedia of Dietary Supplements, 2nd ed.; Informa Healthcare: London, UK, 2010.
54. Vukovich, M.D.; Schoorman, R.; Heilman, C.; Jacob, P., 3rd; Benowitz, N.L. Caffeine-herbal
ephedra combination increases resting energy expenditure, heart rate and blood pressure. Clin.
Exp. Pharmacol. Physiol. 2005, 32, 47–53.
55. Nightingale, S.L. From the Food and Drug Administration. JAMA 1997, 278, 15.
56. Haller, C.A.; Benowitz, N.L. Adverse cardiovascular and central nervous system events
associated with dietary supplements containing ephedra alkaloids. N. Engl. J. Med. 2000, 343,
1833–1838.
57. Soni, M.G.; Carabin, I.G.; Griffiths, J.C.; Burdock, G.A. Safety of ephedra: Lessons learned.
Toxicol. Lett. 2004, 150, 97–110.
58. Gurley, B.J.; Gardner, S.F.; White, L.M.; Wang, P.L. Ephedrine pharmacokinetics after the
ingestion of nutritional supplements containing Ephedra sinica (ma huang). Ther. Drug Monit.
1998, 20, 439–445.
59. Stevinson, C.; Pittler, M.H.; Ernst, E. Garlic for treating hypercholesterolemia. A meta-analysis
of randomized clinical trials. Ann. Intern. Med. 2000, 133, 420–429.
60. Rybak, M.E.; Calvey, E.M.; Harnly, J.M. Quantitative determination of allicin in garlic:
Supercritical fluid extraction and standard addition of alliin. J. Agric. Food Chem. 2004, 52,
682–687.
61. Chan, K.C.; Yin, M.C.; Chao, W.J. Effect of diallyl trisulfide-rich garlic oil on blood coagulation
and plasma activity of anticoagulation factors in rats. Food Chem. Toxicol. 2007, 45, 502–507.
62. Fukao, H.; Yoshida, H.; Tazawa, Y.; Hada, T. Antithrombotic effects of odorless garlic powder
both in vitro and in vivo. Biosci. Biotechnol. Biochem. 2007, 71, 84–90.
63. Rahman, K. Effects of garlic on platelet biochemistry and physiology. Mol. Nutr. Food Res. 2007,
51, 1335–1344.
64. Scharbert, G.; Kalb Madeleine, L.; Duris, M.; Marschalek, C.; Kozek-Langenecker Sibylle, A.
Garlic at dietary doses does not impair platelet function. Anesth. Analg. 2007, 105, 1214–1218,
table of contents.
65. Borrelli, F.; Capasso, R.; Izzo, A.A. Garlic (Allium sativum L.): Adverse effects and drug
interactions in humans. Mol. Nutr. Food Res. 2007, 51, 1386–1397.
66. Sunter, W.H. Warfarin and garlic. Pharm. J. 1991, 246, 722.
67. Reinhart, K.M.; Coleman, C.I.; Teevan, C.; Vachhani, P.; White, C.M. Effects of garlic on blood
pressure in patients with and without systolic hypertension: A meta-analysis. Ann. Pharmacother.
2008, 42, 1766–1771.
68. Lachmann, G.; Lorenz, D.; Radeck, W.; Steiper, M. The pharmacokinetics of the S35 labeled
labeled garlic constituents alliin, allicin and vinyldithiine. Arzneim. Forsch. 1994, 44, 734–743.
69. Gurley, B.J.; Gardner, S.F.; Hubbard, M.A.; Williams, D.K.; Gentry, W.B.; Cui, Y.; Ang, C.Y.
Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans.
Clin. Pharmacol. Ther. 2002, 72, 276–287.
70. Shi, S.; Klotz, U. Drug interactions with herbal medicines. Clin. Pharmacokinet. 2012, 51,
77–104.
71. Berginc, K.; Kristl, A. The effect of garlic supplements and phytochemicals on the ADMET
properties of drugs. Expert Opin. Drug Metab. Toxicol. 2012, 8, 295–310.
72. Huang, C.F.; Yang, R.S.; Liu, S.H.; Hsieh, P.C.; Lin-Shiau, S.Y. Evidence for improved
neuropharmacological efficacy and decreased neurotoxicity in mice with traditional processing of
Rhizoma Arisaematis. Am. J. Chin. Med. 2011, 39, 981–998.
73. Al-Suhaimi, E.A.; Al-Riziza, N.A.; Al-Essa, R.A. Physiological and therapeutical roles of ginger
and turmeric on endocrine functions. Am. J. Chin. Med. 2011, 39, 215–231.
74. Saenghong, N.; Wattanathorn, J.; Muchimapura, S.; Tongun, T.; Piyavhatkul, N.;
Banchonglikitkul, C.; Kajsongkram, T. Zingiber officinale Improves Cognitive Function of the
Middle-Aged Healthy Women. Evid. Based Complement. Alternat. Med. 2012, 2012, 383062.
75. Ali, B.H.; Blunden, G.; Tanira, M.O.; Nemmar, A. Some phytochemical, pharmacological and
toxicological properties of ginger (Zingiber officinale Roscoe): A review of recent research.
Food Chem. Toxicol. 2008, 46, 409–420.
76. Koo, K.L.; Ammit, A.J.; Tran, V.H.; Duke, C.C.; Roufogalis, B.D. Gingerols and related
analogues inhibit arachidonic acid-induced human platelet serotonin release and aggregation.
Thromb. Res. 2001, 103, 387–397.
77. Pongrojpaw, D.; Chiamchanya, C. The efficacy of ginger in prevention of post-operative nausea
and vomiting after outpatient gynecological laparoscopy. J. Med. Assoc. Thai. 2003, 86, 244–250.
78. Nurtjahja-Tjendraputra, E.; Ammit, A.J.; Roufogalis, B.D.; Tran, V.H.; Duke, C.C. Effective
anti-platelet and COX-1 enzyme inhibitors from pungent constituents of ginger. Thromb. Res.
2003, 111, 259–265.
79. Kruth, P.; Brosi, E.; Fux, R.; Morike, K.; Gleiter, C.H. Ginger-associated overanticoagulation by
phenprocoumon. Ann. Pharmacother. 2004, 38, 257–260.
80. Young, H.Y.; Liao, J.C.; Chang, Y.S.; Luo, Y.L.; Lu, M.C.; Peng, W.H. Synergistic effect of
ginger and nifedipine on human platelet aggregation: A study in hypertensive patients and
normal volunteers. Am. J. Chin. Med. 2006, 34, 545–551.
81. van Beek, T.A.; Montoro, P. Chemical analysis and quality control of Ginkgo biloba leaves,
extracts, and phytopharmaceuticals. J. Chromatogr. A 2009, 1216, 2002–2032.
82. Koh, P.O. Identification of proteins differentially expressed in cerebral cortexes of Ginkgo biloba
extract (EGb761)-treated rats in a middle cerebral artery occlusion model—A proteomics
approach. Am. J. Chin. Med. 2011, 39, 315–324.
83. Koh, P.O. Gingko biloba extract (EGb 761) attenuates the focal cerebral ischemic injury-induced
decrease in astrocytic phosphoprotein PEA-15 levels. Am. J. Chin. Med. 2011, 39, 971–979.
84. Koh, P.O. Gingko biloba extract (EGb 761) prevents cerebral ischemia-induced p70S6 kinase
and S6 phosphorylation. Am. J. Chin. Med. 2010, 38, 727–734.
85. Fransen, H.P.; Pelgrom, S.M.; Stewart-Knox, B.; de Kaste, D.; Verhagen, H. Assessment of
health claims, content, and safety of herbal supplements containing Ginkgo biloba. Food Nutr. Res.
2010, 54, doi:10.3402/fnr.v54i0.5221.
86. Le Bars, P.L.; Katz, M.M.; Berman, N.; Itil, T.M.; Freedman, A.M.; Schatzberg, A.F.
A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia.
North American EGb Study Group. JAMA 1997, 278, 1327–1332.
87. Solomon, P.R.; Adams, F.; Silver, A.; Zimmer, J.; deVeaux, R. Ginkgo for memory enhancement:
A randomized controlled trial. JAMA 2002, 288, 835–840.
88. Ude, C.; Paulke, A.; Noldner, M.; Schubert-Zsilavecz, M.; Wurglics, M. Plasma and brain levels
of terpene trilactones in rats after an oral single dose of standardized Ginkgo biloba extract EGb
761(R). Planta Med. 2011, 77, 259–264.
89. Kim, Y.S.; Pyo, M.K.; Park, K.M.; Park, P.H.; Hahn, B.S.; Wu, S.J.; Yun-Choi, H.S. Antiplatelet
and antithrombotic effects of a combination of ticlopidine and ginkgo biloba ext (EGb 761).
Thromb. Res. 1998, 91, 33–38.
90. Sasaki, Y.; Noguchi, T.; Yamamoto, E.; Giddings, J.C.; Ikeda, K.; Yamori, Y.; Yamamoto, J.
Effects of Ginkgo biloba extract (EGb 761) on cerebral thrombosis and blood pressure in
stroke-prone spontaneously hypertensive rats. Clin. Exp. Pharmacol. Physiol. 2002, 29, 963–967.
91. Guinot, P.; Caffrey, E.; Lambe, R.; Darragh, A. Tanakan inhibits platelet-activating-factor-
induced platelet aggregation in healthy male volunteers. Haemostasis 1989, 19, 219–223.
92. Kohler, S.; Funk, P.; Kieser, M. Influence of a 7-day treatment with Ginkgo biloba special
extract EGb 761 on bleeding time and coagulation: A randomized, placebo-controlled, double-
blind study in healthy volunteers. Blood Coagul. Fibrinolysis 2004, 15, 303–309.
93. Beckert, B.W.; Concannon, M.J.; Henry, S.L.; Smith, D.S.; Puckett, C.L. The effect of
herbal medicines on platelet function: An in vivo experiment and review of the literature.
Plast. Reconstr. Surg. 2007, 120, 2044–2050.
94. Pedroso, J.L.; Henriques Aquino, C.C.; Escorcio Bezerra, M.L.; Baiense, R.F.; Suarez, M.M.;
Dutra, L.A.; Braga-Neto, P.; Povoas Barsottini, O.G. Ginkgo biloba and cerebral bleeding: A
case report and critical review. Neurologist 2011, 17, 89–90.
95. Rosenblatt, M.; Mindel, J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract.
N. Engl. J. Med. 1997, 336, 1108.
96. Fessenden, J.M.; Wittenborn, W.; Clarke, L. Gingko biloba: A case report of herbal medicine and
bleeding postoperatively from a laparoscopic cholecystectomy. Am. Surg. 2001, 67, 33–35.
97. Drago, F.; Floriddia, M.L.; Cro, M.; Giuffrida, S. Pharmacokinetics and bioavailability of a
Ginkgo biloba extract. J. Ocul. Pharmacol. Ther. 2002, 18, 197–202.
98. Nagappan, A.; Karunanithi, N.; Sentrayaperumal, S.; Park, K.I.; Park, H.S.; Lee do, H.;
Kang, S.R.; Kim, J.A.; Senthil, K.; Natesan, S.; et al. Comparative root protein profiles of
Korean ginseng (Panax ginseng) and Indian ginseng (Withania somnifera). Am. J. Chin. Med.
2012, 40, 203–218.
99. Attele, A.S.; Wu, J.A.; Yuan, C.S. Ginseng pharmacology: Multiple constituents and multiple
actions. Biochem. Pharmacol. 1999, 58, 1685–1693.
100. Hwang, J.W.; Oh, J.H.; Yoo, H.S.; Lee, Y.W.; Cho, C.K.; Kwon, K.R.; Yoon, J.H.; Park, J.;
Her, S.; Lee, Z.W.; et al. Mountain ginseng extract exhibits anti-lung cancer activity by
inhibiting the nuclear translocation of NF-kappaB. Am. J. Chin. Med. 2012, 40, 187–202.
101. Shergis, J.L.; Zhang, A.L.; Zhou, W.; Xue, C.C. Quality and risk of bias in Panax ginseng
randomized controlled trials: A review. Am. J. Chin. Med. 2013, 41, 231–252.
102. Zhang, H.M.; Li, S.L.; Zhang, H.; Wang, Y.; Zhao, Z.L.; Chen, S.L.; Xu, H.X. Holistic quality
evaluation of commercial white and red ginseng using a UPLC-QTOF-MS/MS-based metabolomics
approach. J. Pharm. Biomed. Anal. 2012, 62, 258–273.
103. Sievenpiper, J.L.; Arnason, J.T.; Leiter, L.A.; Vuksan, V. Null and opposing effects of Asian
ginseng (Panax ginseng C.A. Meyer) on acute glycemia: Results of two acute dose escalation
studies. J. Am. Coll. Nutr. 2003, 22, 524–532.
104. Sengupta, S.; Toh, S.A.; Sellers, L.A.; Skepper, J.N.; Koolwijk, P.; Leung, H.W.; Yeung, H.W.;
Wong, R.N.; Sasisekharan, R.; Fan, T.P. Modulating angiogenesis: The yin and the yang in
ginseng. Circulation 2004, 110, 1219–1225.
105. Attele, A.S.; Zhou, Y.P.; Xie, J.T.; Wu, J.A.; Zhang, L.; Dey, L.; Pugh, W.; Rue, P.A.;
Polonsky, K.S.; Yuan, C.S. Antidiabetic effects of Panax ginseng berry extract and the
identification of an effective component. Diabetes 2002, 51, 1851–1858.
106. Xie, J.T.; Wang, C.Z.; Ni, M.; Wu, J.A.; Mehendale, S.R.; Aung, H.H.; Foo, A.; Yuan, C.S.
American ginseng berry juice intake reduces blood glucose and body weight in ob/ob mice.
J. Food Sci. 2007, 72, S590–S594.
107. Torbey, E.; Abi Rafeh, N.; Khoueiry, G.; Kowalski, M.; Bekheit, S. Ginseng: A potential cause
of long QT. J. Electrocardiol. 2011, 44, 357–358.
108. Teng, C.M.; Kuo, S.C.; Ko, F.N.; Lee, J.C.; Lee, L.G.; Chen, S.C.; Huang, T.F. Antiplatelet
actions of panaxynol and ginsenosides isolated from ginseng. Biochim. Biophys. Acta 1989, 990,
315–320.
109. Lee, W.M.; Kim, S.D.; Park, M.H.; Cho, J.Y.; Park, H.J.; Seo, G.S.; Rhee, M.H. Inhibitory
mechanisms of dihydroginsenoside Rg3 in platelet aggregation: Critical roles of ERK2 and
cAMP. J. Pharm. Pharmacol. 2008, 60, 1531–1536.
110. Lee, J.G.; Lee, Y.Y.; Kim, S.Y.; Pyo, J.S.; Yun-Choi, H.S.; Park, J.H. Platelet antiaggregating
activity of ginsenosides isolated from processed ginseng. Pharmazie 2009, 64, 602–604.
111. Jin, Y.R.; Yu, J.Y.; Lee, J.J.; You, S.H.; Chung, J.H.; Noh, J.Y.; Im, J.H.; Han, X.H.; Kim, T.J.;
Shin, K.S.; et al. Antithrombotic and antiplatelet activities of Korean red ginseng extract.
Basic Clin. Pharmacol. Toxicol. 2007, 100, 170–175.
112. Endale, M.; Lee, W.; Kamruzzaman, S.; Kim, S.; Park, J.; Park, M.; Park, T.; Park, H.; Cho, J.;
Rhee, M. Ginsenoside-Rp1 inhibits platelet activation and thrombus formation via impaired
GPVI signaling pathway tyrosine phosphorylation and MAPK activation. Br. J. Pharmacol. 2012,
167, 109–127.
113. Janetzky, K.; Morreale, A.P. Probable interaction between warfarin and ginseng. Am. J. Health.
Syst. Pharm. 1997, 54, 692–693.
114. Yuan, C.S.; Wei, G.; Dey, L.; Karrison, T.; Nahlik, L.; Maleckar, S.; Kasza, K.; Ang-Lee, M.;
Moss, J. Brief communication: American ginseng reduces warfarin’s effect in healthy patients:
A randomized, controlled Trial. Ann. Intern. Med. 2004, 141, 23–27.
115. Jiang, X.; Blair, E.Y.; McLachlan, A.J. Investigation of the effects of herbal medicines on
warfarin response in healthy subjects: A population pharmacokinetic-pharmacodynamic
modeling approach. J. Clin. Pharmacol. 2006, 46, 1370–1378.
116. Li, X.; Sun, J.; Wang, G.; Hao, H.; Liang, Y.; Zheng, Y.; Yan, B.; Sheng, L. Simultaneous
determination of panax notoginsenoside R1, ginsenoside Rg1, Rd, Re and Rb1 in rat plasma by
HPLC/ESI/MS: Platform for the pharmacokinetic evaluation of total panax notoginsenoside, a
typical kind of multiple constituent traditional Chinese medicine. Biomed. Chromatogr. 2007, 21,
735–746.
117. Munekage, M.; Kitagawa, H.; Ichikawa, K.; Watanabe, J.; Aoki, K.; Kono, T.; Hanazaki, K.
Pharmacokinetics of daikenchuto, a traditional Japanese medicine (kampo) after single oral
administration to healthy Japanese volunteers. Drug Metab. Dispos. 2011, 39, 1784–1788.
118. Wang, C.Z.; Kim, K.E.; Du, G.J.; Qi, L.W.; Wen, X.D.; Li, P.; Bauer, B.A.; Bissonnette, M.B.;
Musch, M.W.; Chang, E.B.; et al. Ultra-performance liquid chromatography and time-of-flight
mass spectrometry analysis of ginsenoside metabolites in human plasma. Am. J. Chin. Med. 2011,
39, 1161–1171.
119. Stote, K.S.; Baer, D.J. Tea consumption may improve biomarkers of insulin sensitivity and risk
factors for diabetes. J. Nutr. 2008, 138, 1584S–1588S.
120. Wang, C.Z.; Mehendale, S.R.; Yuan, C.S. Commonly used antioxidant botanicals: Active
constituents and their potential role in cardiovascular illness. Am. J. Chin. Med. 2007, 35,
543–558.
121. Kang, W.S.; Lim, I.H.; Yuk, D.Y.; Chung, K.H.; Park, J.B.; Yoo, H.S.; Yun, Y.P.
Antithrombotic activities of green tea catechins and (−)-epigallocatechin gallate. Thromb. Res.
1999, 96, 229–237.
122. Son, D.J.; Cho, M.R.; Jin, Y.R.; Kim, S.Y.; Park, Y.H.; Lee, S.H.; Akiba, S.; Sato, T.; Yun, Y.P.
Antiplatelet effect of green tea catechins: A possible mechanism through arachidonic acid
pathway. Prostaglandins Leukot. Essent. Fatty Acids 2004, 71, 25–31.
123. Jin, Y.R.; Im, J.H.; Park, E.S.; Cho, M.R.; Han, X.H.; Lee, J.J.; Lim, Y.; Kim, T.J.; Yun, Y.P.
Antiplatelet activity of epigallocatechin gallate is mediated by the inhibition of PLCgamma2
phosphorylation, elevation of PGD2 production, and maintaining calcium-ATPase activity.
J. Cardiovasc. Pharmacol. 2008, 51, 45–54.
124. Liatsos, G.D.; Moulakakis, A.; Ketikoglou, I.; Klonari, S. Possible green tea-induced thrombotic
thrombocytopenic purpura. Am. J. Health Syst. Pharm. 2010, 67, 531–534.
125. Taylor, J.R.; Wilt, V.M. Probable antagonism of warfarin by green tea. Ann. Pharmacother. 1999,
33, 426–428.
126. Ullmann, U.; Haller, J.; Decourt, J.P.; Girault, N.; Girault, J.; Richard-Caudron, A.S.; Pineau, B.;
Weber, P. A single ascending dose study of epigallocatechin gallate in healthy volunteers. J. Int.
Med. Res. 2003, 31, 88–101.
127. Gawande, S.; Kale, A.; Kotwal, S. Effect of nutrient mixture and black grapes on the
pharmacokinetics of orally administered (−)epigallocatechin-3-gallate from green tea extract:
A human study. Phytother. Res. 2008, 22, 802–808.
128. Singh, Y.N.; Singh, N.N. Therapeutic potential of kava in the treatment of anxiety disorders.
CNS Drugs 2002, 16, 731–743.
129. Johnson, T.E.; Hermanson, D.; Wang, L.; Kassie, F.; Upadhyaya, P.; O’Sullivan, M.G.; Hecht, S.S.;
Lu, J.; Xing, C. Lung tumorigenesis suppressing effects of a commercial kava extract and its
selected compounds in A/J mice. Am. J. Chin. Med. 2011, 39, 727–742.
130. Yuan, C.S.; Dey, L.; Wang, A.; Mehendale, S.; Xie, J.T.; Aung, H.H.; Ang-Lee, M.K.
Kavalactones and dihydrokavain modulate GABAergic activity in a rat gastric-brainstem
preparation. Planta Med. 2002, 68, 1092–1096.
131. Jamieson, D.D.; Duffield, P.H.; Cheng, D.; Duffield, A.M. Comparison of the central nervous
system activity of the aqueous and lipid extract of kava (Piper methysticum). Arch. Int.
Pharmacodyn. Ther. 1989, 301, 66–80.
132. Almeida, J.C.; Grimsley, E.W. Coma from the health food store: Interaction between kava and
alprazolam. Ann. Intern. Med. 1996, 125, 940–941.
133. Brown, A.C.; Onopa, J.; Holck, P.; Kaufusi, P.; Kabasawa, D.; Craig, W.J.; Dragull, K.; Levine,
A.M.; Baker, J.D. Traditional kava beverage consumption and liver function tests in a
predominantly Tongan population in Hawaii. Clin. Toxicol. (Phila) 2007, 45, 549–556.
134. Teschke, R.; Schulze, J. Risk of kava hepatotoxicity and the FDA consumer advisory. JAMA
2010, 304, 2174–2175.
135. Gounder, R. Kava consumption and its health effects. Pac. Health Dialog. 2006, 13, 131–135.
136. Gleitz, J.; Beile, A.; Wilkens, P.; Ameri, A.; Peters, T. Antithrombotic action of the kava pyrone
(+)-kavain prepared from Piper methysticum on human platelets. Planta Med. 1997, 63, 27–30.
137. Mathews, J.D.; Riley, M.D.; Fejo, L.; Munoz, E.; Milns, N.R.; Gardner, I.D.; Powers, J.R.;
Ganygulpa, E.; Gununuwawuy, B.J. Effects of the heavy usage of kava on physical health:
Summary of a pilot survey in an aboriginal community. Med. J. Aust. 1988, 148, 548–555.
138. Pepping, J. Kava: Piper methysticum. Am. J. Health. Syst. Pharm. 1999, 56, 957–958, 960.
139. Raduege, K.M.; Kleshinski, J.F.; Ryckman, J.V.; Tetzlaff, J.E. Anesthetic considerations of the
herbal, kava. J. Clin. Anesth. 2004, 16, 305–311.
140. Russmann, S.; Lauterburg, B.H.; Helbling, A. Kava hepatotoxicity. Ann. Intern. Med. 2001, 135,
68–69.
141. Escher, M.; Desmeules, J.; Giostra, E.; Mentha, G. Hepatitis associated with Kava, a herbal
remedy for anxiety. BMJ 2001, 322, 139.
142. Mathews, J.M.; Etheridge, A.S.; Valentine, J.L.; Black, S.R.; Coleman, D.P.; Patel, P.; So, J.;
Burka, L.T. Pharmacokinetics and disposition of the kavalactone kawain: Interaction with kava
extract and kavalactones in vivo and in vitro. Drug Metab. Dispos. 2005, 33, 1555–1563.
143. Bent, S.; Kane, C.; Shinohara, K.; Neuhaus, J.; Hudes, E.S.; Goldberg, H.; Avins, A.L.
Saw palmetto for benign prostatic hyperplasia. N. Engl. J. Med. 2006, 354, 557–566.
144. Geavlete, P.; Multescu, R.; Geavlete, B. Serenoa repens extract in the treatment of benign
prostatic hyperplasia. Ther. Adv. Urol. 2011, 3, 193–198.
145. Oki, T.; Suzuki, M.; Nishioka, Y.; Yasuda, A.; Umegaki, K.; Yamada, S. Effects of saw palmetto
extract on micturition reflex of rats and its autonomic receptor binding activity. J. Urol. 2005,
173, 1395–1399.
146. Cheema, P.; el-Mefty, O.; Jazieh, A.R. Intraoperative haemorrhage associated with the use of
extract of Saw Palmetto herb: A case report and review of literature. J. Intern. Med. 2001, 250,
167–169.
147. Villanueva, S.; Gonzalez, J. Coagulopathy induced by saw palmetto: A case report. Boletin 2009,
101, 48–50.
148. Freeman, M.P.; Fava, M.; Lake, J.; Trivedi, M.H.; Wisner, K.L.; Mischoulon, D. Complementary
and alternative medicine in major depressive disorder: The American Psychiatric Association
Task Force report. J. Clin. Psychiatry 2010, 71, 669–681.
149. Karioti, A.; Bilia, A.R. Hypericins as potential leads for new therapeutics. Int. J. Mol. Sci. 2010,
11, 562–594.
150. Lawvere, S.; Mahoney, M.C. St. John’s wort. Am. Fam. Physician 2005, 72, 2249–2254.
151. Zanoli, P. Role of hyperforin in the pharmacological activities of St. John’s Wort. CNS Drug Rev.
2004, 10, 203–218.
152. Izzo, A.A. Drug interactions with St. John’s Wort (Hypericum perforatum): A review of the
clinical evidence. Int. J. Clin. Pharmacol. Ther. 2004, 42, 139–148.
153. Yoshitake, T.; Iizuka, R.; Yoshitake, S.; Weikop, P.; Muller, W.E.; Ogren, S.O.; Kehr, J.
Hypericum perforatum L (St John’s wort) preferentially increases extracellular dopamine levels
in the rat prefrontal cortex. Br. J. Pharmacol. 2004, 142, 414–418.
154. Schellander, R.; Donnerer, J. Antidepressants: Clinically relevant drug interactions to be considered.
Pharmacology 2010, 86, 203–215.
155. Ernst, E. Second thoughts about safety of St John’s wort. Lancet 1999, 354, 2014–2016.
156. Pal, D.; Mitra, A.K. MDR- and CYP3A4-mediated drug-herbal interactions. Life Sci. 2006, 78,
2131–2145.
157. Piscitelli, S.C.; Burstein, A.H.; Chaitt, D.; Alfaro, R.M.; Falloon, J. Indinavir concentrations and
St John’s wort. Lancet 2000, 355, 547–548.
158. Yue, Q.Y.; Bergquist, C.; Gerden, B. Safety of St John’s wort (Hypericum perforatum). Lancet
2000, 355, 576–577.
159. Ruschitzka, F.; Meier, P.J.; Turina, M.; Luscher, T.F.; Noll, G. Acute heart transplant rejection
due to Saint John’s wort. Lancet 2000, 355, 548–549.
160. Breidenbach, T.; Hoffmann, M.W.; Becker, T.; Schlitt, H.; Klempnauer, J. Drug interaction of
St John’s wort with cyclosporin. Lancet 2000, 355, 1912.
161. Dasgupta, A. Herbal supplements and therapeutic drug monitoring: Focus on digoxin immunoassays
and interactions with St. John’s wort. Ther. Drug Monit. 2008, 30, 212–217.
162. Hu, Z.P.; Yang, X.X.; Chen, X.; Cao, J.; Chan, E.; Duan, W.; Huang, M.; Yu, X.Q.; Wen, J.Y.;
Zhou, S.F. A mechanistic study on altered pharmacokinetics of irinotecan by St. John’s wort.
Curr. Drug Metab. 2007, 8, 157–171.
163. Hall, S.D.; Wang, Z.; Huang, S.M.; Hamman, M.A.; Vasavada, N.; Adigun, A.Q.; Hilligoss, J.K.;
Miller, M.; Gorski, J.C. The interaction between St John’s wort and an oral contraceptive.
Clin. Pharmacol. Ther. 2003, 74, 525–535.
164. Murphy, P.A.; Kern, S.E.; Stanczyk, F.Z.; Westhoff, C.L. Interaction of St. John’s Wort with oral
contraceptives: Effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian
activity and breakthrough bleeding. Contraception 2005, 71, 402–408.
165. Crampsey, D.P.; Douglas, C.M.; Cooke, L.D. Nasal insertion of St John’s wort: An unusual
cause of epistaxis. J. Laryngol. Otol. 2007, 121, 279–280.
166. Wurglics, M.; Schubert-Zsilavecz, M. Hypericum perforatum: A “modern” herbal antidepressant:
Pharmacokinetics of active ingredients. Clin. Pharmacokinet. 2006, 45, 449–468.
167. Salter, S.; Brownie, S. Treating primary insomnia—The efficacy of valerian and hops.
Aust. Fam. Physician 2010, 39, 433–437.
168. Ortiz, J.G.; Rassi, N.; Maldonado, P.M.; Gonzalez-Cabrera, S.; Ramos, I. Commercial valerian
interactions with [3H]Flunitrazepam and [3H]MK-801 binding to rat synaptic membranes.
Phytother. Res. 2006, 20, 794–798.
169. Wheatley, D. Medicinal plants for insomnia: A review of their pharmacology, efficacy and
tolerability. J. Psychopharmacol. 2005, 19, 414–421.
170. Yuan, C.S.; Mehendale, S.; Xiao, Y.; Aung, H.H.; Xie, J.T.; Ang-Lee, M.K. The gamma-
aminobutyric acidergic effects of valerian and valerenic acid on rat brainstem neuronal activity.
Anesth. Analg. 2004, 98, 353–358, table of contents.
171. Leuschner, J.; Muller, J.; Rudmann, M. Characterisation of the central nervous depressant
activity of a commercially available valerian root extract. Arzneim. Forsch. 1993, 43, 638–641.
172. Gooneratne, N.S. Complementary and alternative medicine for sleep disturbances in older adults.
Clin. Geriatr. Med. 2008, 24, 121–138, viii.
173. Taavoni, S.; Ekbatani, N.; Kashaniyan, M.; Haghani, H. Effect of valerian on sleep quality in
postmenopausal women: A randomized placebo-controlled clinical trial. Menopause 2011, 18,
951–955.
174. Taibi, D.M.; Landis, C.A.; Petry, H.; Vitiello, M.V. A systematic review of valerian as a sleep
aid: Safe but not effective. Sleep Med. Rev. 2007, 11, 209–230.
175. Garges, H.P.; Varia, I.; Doraiswamy, P.M. Cardiac complications and delirium associated with
valerian root withdrawal. JAMA 1998, 280, 1566–1567.
176. Anderson, G.D.; Elmer, G.W.; Kantor, E.D.; Templeton, I.E.; Vitiello, M.V. Pharmacokinetics of
valerenic acid after administration of valerian in healthy subjects. Phytother. Res. 2005, 19,
801–803.
177. Anderson, G.D.; Elmer, G.W.; Taibi, D.M.; Vitiello, M.V.; Kantor, E.; Kalhorn, T.F.; Howald, W.N.;
Barsness, S.; Landis, C.A. Pharmacokinetics of valerenic acid after single and multiple doses of
valerian in older women. Phytother. Res. 2010, 24, 1442–1446.
178. Cohen, D.L.; del Toro, Y. A case of valerian-associated hepatotoxicity. J. Clin. Gastroenterol.
2008, 42, 961–962.
179. Basila, D.; Yuan, C.S. Effects of dietary supplements on coagulation and platelet function.
Thromb. Res. 2005, 117, 49–53; discussion 65–47.
180. Ling, S.; Dai, A.; Guo, Z.; Yan, X.; Komesaroff, P.A. Effects of a Chinese herbal preparation on
vascular cells in culture: Mechanisms of cardiovascular protection. Clin. Exp. Pharm. Physiol.
2005, 32, 571–578.
181. Gao, Z.Y.; Xu, H.; Shi, D.Z.; Wen, C.; Liu, B.Y. Analysis on outcome of 5284 patients with
coronary artery disease: The role of integrative medicine. J. Ethnopharmacol. 2012, 141,
578–583.
182. Zhang, H.C.; Liu, W.; Yuan, H.T.; Tang, Y.S. Salvia Miltiorrhiza reduces plasma levels of
asymmetric ADMA in patients with non-ST elevation myocardial infarction undergoing
percutaneous coronary intervention. Zhongguo Zhong Xi Yi Jie He Za Zhi 2014, 34, 1436–1439.
183. Chen, J.; Lv, Q.; Yu, M.; Zhang, X.; Gou, J. Randomized clinical trial of Chinese herbal
medications to reduce wound complications after mastectomy for breast carcinoma. Br. J. Surg.
2010, 97, 1798–1804.
184. Luo, H.W.; Hu, X.J.; Wang, N.; Ji, J. Platelet aggregation inhibitors from Salvia miltiorrhiza
Bunge. Yao Xue Xue Bao 1988, 23, 830–834.
185. Maione, F.; de Feo, V.; Caiazzo, E.; de Martino, L.; Cicala, C.; Mascolo, N. Tanshinone IIA,
a major component of Salvia milthorriza Bunge, inhibits platelet activation via Erk-2 signaling
pathway. J. Ethnopharmacol. 2014, 155, 1236–1242.
186. Maione, F.; Cantone, V.; Chini, M.G.; de Feo, V.; Mascolo, N.; Bifulco, G. Molecular
mechanism of tanshinone IIA and cryptotanshinone in platelet anti-aggregating effects: An
integrated study of pharmacology and computational analysis. Fitoterapia 2015, 100, 174–178.
187. Zhou, S.; Chan, E. Effect of ubidecarenone on warfarin anticoagulation and pharmacokinetics of
warfarin enantiomers in rats. Drug Metab. Drug Interact. 2001, 18, 99–122.
188. Zhou, Q.; Zhou, S.; Chan, E. Effect of coenzyme Q10 on warfarin hydroxylation in rat and
human liver microsomes. Curr. Drug Metab. 2005, 6, 67–81.
189. Spigset, O. Reduced effect of warfarin caused by ubidecarenone. Lancet 1994, 344, 1372–1373.
190. Engelsen, J.; Nielsen, J.D.; Hansen, K.F. Effect of Coenzyme Q10 and Ginkgo biloba on
warfarin dosage in patients on long-term warfarin treatment. A randomized, double-blind, placebo-
controlled cross-over trial. Ugeskr. Laeger 2003, 165, 1868–1871.
191. Shalansky, S.; Lynd, L.; Richardson, K.; Ingaszewski, A.; Kerr, C. Risk of warfarin-related
bleeding events and supratherapeutic international normalized ratios associated with complementary
and alternative medicine: A longitudinal analysis. Pharmacotherapy 2007, 27, 1237–1247.
192. Evans, M.; Sharma, P.; Guthrie, N. A randomized, double-blind, crossover study on the
pharmacokinetics of a novel formulation of CoQ(1)(0) with pyridoxal 5ʹ-phosphate and
phosphatidyl choline. J. Diet Suppl. 2010, 7, 314–324.
193. Huskisson, E.C. Glucosamine and chondroitin for osteoarthritis. J. Int. Med. Res. 2008, 36,
1161–1179.
194. Miller, K.L.; Clegg, D.O. Glucosamine and chondroitin sulfate. Rheum. Dis. Clin. North Am.
2011, 37, 103–118.
195. Clegg, D.O.; Reda, D.J.; Harris, C.L.; Klein, M.A.; O’Dell, J.R.; Hooper, M.M.; Bradley, J.D.;
Bingham, C.O., 3rd; Weisman, M.H.; Jackson, C.G.; et al. Glucosamine, chondroitin sulfate, and
the two in combination for painful knee osteoarthritis. N. Engl. J. Med. 2006, 354, 795–808.
196. Tang, J.; Neidigh, J.L.; Cooksey, R.C.; McClain, D.A. Transgenic mice with increased
hexosamine flux specifically targeted to beta-cells exhibit hyperinsulinemia and peripheral
insulin resistance. Diabetes 2000, 49, 1492–1499.
197. Scroggie, D.A.; Albright, A.; Harris, M.D. The effect of glucosamine-chondroitin
supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: A
placebo-controlled, double-blinded, randomized clinical trial. Arch. Intern. Med. 2003, 163,
1587–1590.
198. Knudsen, J.F.; Sokol, G.H. Potential glucosamine-warfarin interaction resulting in increased
international normalized ratio: Case report and review of the literature and MedWatch database.
Pharmacotherapy 2008, 28, 540–548.
199. Setnikar, I.; Rovati, L.C. Absorption, distribution, metabolism and excretion of glucosamine
sulfate. A review. Arzneim. Forsch. 2001, 51, 699–725.
200. Persiani, S.; Rotini, R.; Trisolino, G.; Rovati, L.C.; Locatelli, M.; Paganini, D.; Antonioli, D.;
Roda, A. Synovial and plasma glucosamine concentrations in osteoarthritic patients following
oral crystalline glucosamine sulphate at therapeutic dose. Osteoarthr. Cartil. 2007, 15, 764–772.
201. Volpi, N. Oral absorption and bioavailability of ichthyic origin chondroitin sulfate in healthy
male volunteers. Osteoarthr. Cartil. 2003, 11, 433–441.
202. Wall, R.; Ross, R.P.; Fitzgerald, G.F.; Stanton, C. Fatty acids from fish: The anti-inflammatory
potential of long-chain omega-3 fatty acids. Nutr. Rev. 2010, 68, 280–289.
203. Bosch, J.; Gerstein, H.C.; Dagenais, G.R.; Diaz, R.; Dyal, L.; Jung, H.; Maggiono, A.P.;
Probstfield, J.; Ramachandran, A.; Riddle, M.C.; et al. n-3 fatty acids and cardiovascular
outcomes in patients with dysglycemia. N. Engl. J. Med. 2012, 367, 309–318.
204. Dyerberg, J. Platelet—Vessel wall interaction: Influence of diet. Philos. Trans. R. Soc. Lond. B
Biol. Sci. 1981, 294, 373–381.
205. Lazarus, S.A.; Garg, M.L. The effects of tomato extract (TE) and omega-3 fatty acids on platelet
cAMP levels and inositol triphosphate (IP(3)) release. Asia Pac. J. Clin. Nutr. 2003, 12, S20.
206. Sarris, G.E.; Fann, J.I.; Sokoloff, M.H.; Smith, D.L.; Loveday, M.; Kosek, J.C.; Stephens, R.J.;
Cooper, A.D.; May, K.; Willis, A.L.; et al. Mechanisms responsible for inhibition of vein-graft
arteriosclerosis by fish oil. Circulation 1989, 80, I109–1123.
207. Thorwest, M.; Balling, E.; Kristensen, S.D.; Aagaard, S.; Hakami, A.; Husted, S.E.; Marqversen, J.;
Hjortdal, V.E. Dietary fish oil reduces microvascular thrombosis in a porcine experimental model.
Thromb. Res. 2000, 99, 203–208.
208. Phang, M.; Sinclair, A.J.; Lincz, L.F.; Garg, M.L. Gender-specific inhibition of platelet aggregation
following omega-3 fatty acid supplementation. Nutr. Metab. Cardiovasc. Dis. 2012, 22, 109–114.
209. Harris, W.S. Expert opinion: Omega-3 fatty acids and bleeding-cause for concern? Am. J.
Cardiol. 2007, 99, S44–S46.
210. Salisbury, A.C.; Harris, W.S.; Amin, A.P.; Reid, K.J.; O’Keefe, J.H., Jr.; Spertus, J.A. Relation
between red blood cell omega-3 fatty acid index and bleeding during acute myocardial infarction.
Am. J. Cardiol. 2012, 109, 13–18.
211. Stanger, M.J.; Thompson, L.A.; Young, A.J.; Lieberman, H.R. Anticoagulant activity of select
dietary supplements. Nutr. Rev. 2012, 70, 107–117.
212. Jalili, M.; Dehpour, A.R. Extremely prolonged INR associated with warfarin in combination with
both trazodone and omega-3 fatty acids. Arch. Med. Res. 2007, 38, 901–904.
213. Buckley, M.S.; Goff, A.D.; Knapp, W.E. Fish oil interaction with warfarin. Ann. Pharmacother.
2004, 38, 50–52.
214. McClaskey, E.M.; Michalets, E.L. Subdural hematoma after a fall in an elderly patient taking
high-dose omega-3 fatty acids with warfarin and aspirin: Case report and review of the literature.
Pharmacotherapy 2007, 27, 152–160.
215. Broughton, G., 2nd; Crosby, M.A.; Coleman, J.; Rohrich, R.J. Use of herbal supplements and
vitamins in plastic surgery: A practical review. Plast. Reconstr. Surg. 2007, 119, 48e–66e.
216. Mehta, J.B.; Singhal, S.B.; Mehta, B.C. Ascorbic-acid-induced haemolysis in G-6-PD deficiency.
Lancet 1990, 336, 944.
217. Rosenthal, G. Interaction of ascorbic acid and warfarin. JAMA 1971, 215, 1671.
218. Weintraub, M.; Griner, P.F. Warfarin and ascorbic acid: Lack of evidence for a drug interaction.
Toxicol. Appl. Pharmacol. 1974, 28, 53–56.
219. Feetam, C.L.; Leach, R.H.; Meynell, M.J. Lack of a clinically important interaction between
warfarin and ascorbic acid. Toxicol. Appl. Pharmacol. 1975, 31, 544–547.
220. Food and Nutrition Board; Institute of Medicine, Dietary Reference Intakes for Vitamin C,
Vitamin E, Selenium, and Carotenoids; National Academy Press: Washington, DC, USA, 2000.
221. Shuster, L.T.; Thielen, J., Evidence-based use of vitamin supplements. In Textbook of
Complementary and Alternative Medicine, 2nd ed.; Yuan, C.S., Bieber, E.J., Bauer, B.A., Eds.;
Informa Healthcare: Abingdon, UK, 2006; pp. 99–108.
222. Cox, A.C.; Rao, G.H.; Gerrard, J.M.; White, J.G. The influence of vitamin E quinone on platelet
structure, function, and biochemistry. Blood 1980, 55, 907–914.
223. Szuwart, T.; Brzoska, T.; Luger, T.A.; Filler, T.; Peuker, E.; Dierichs, R. Vitamin E reduces
platelet adhesion to human endothelial cells in vitro. Am. J. Hematol. 2000, 65, 1–4.
224. Corrigan, J.J., Jr.; Ulfers, L.L. Effect of vitamin E on prothrombin levels in warfarin-induced
vitamin K deficiency. Am. J. Clin. Nutr. 1981, 34, 1701–1705.
225. Kim, J.M.; White, R.H. Effect of vitamin E on the anticoagulant response to warfarin. Am. J. Cardiol.
1996, 77, 545–546.
226. Booth, S.L.; Golly, I.; Sacheck, J.M.; Roubenoff, R.; Dallal, G.E.; Hamada, K.; Blumberg, J.B.
Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status.
Am. J. Clin. Nutr. 2004, 80, 143–148.
227. Steiner, M.; Glantz, M.; Lekos, A. Vitamin E plus aspirin compared with aspirin alone in patients
with transient ischemic attacks. Am. J. Clin. Nutr. 1995, 62, 1381S–1384S.
228. Dereska, N.H.; McLemore, E.C.; Tessier, D.J.; Bash, D.S.; Brophy, C.M. Short-term, moderate
dosage Vitamin E supplementation may have no effect on platelet aggregation, coagulation
profile, and bleeding time in healthy individuals. J. Surg. Res. 2006, 132, 121–129.
229. Kaye, A.D.; Kucera, I.; Sabar, R. Perioperative anesthesia clinical considerations of alternative
medicines. Anesthesiol. Clin. North Am. 2004, 22, 125–139.
230. Reddy, V.Y.; Sievert, H.; Halperin, J.; Doshi, S.K.; Buchbinder, M.; Neuzil, P.; Huber, K.;
Whisenant, B.; Kar, S.; Swarup, V.; et al. Percutaneous left atrial appendage closure vs. warfarin
for atrial fibrillation: A randomized clinical trial. JAMA 2014, 312, 1988–1998.
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/4.0/).

Medicines: Commonly Used Dietary Supplements On Coagulation Function During Surgery

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Medicines: Commonly Used Dietary Supplements On Coagulation Function During Surgery

Uploaded by

Copyright:

Available Formats

Medicines 2015, 2, 157-185; doi:10.

Commonly Used Dietary Supplements on Coagulation Function

* Author to whom correspondence should be addressed; E-Mail: czwang@uchicago.edu;

Academic Editor: James D. Adams

Received: 30 May 2015 / Accepted: 22 July 2015 / Published: 27 July 2015

Background: Patients who undergo surgery appear to use dietary supplements

ginseng, and kava. Pharmacodynamic and pharmacokinetic interactions between dietary

Conclusions: To prevent potential problems associated with the use of dietary

Keywords: dietary supplements; natural products; surgery; coagulation; platelet

2.1. Database and Search Strategies

2.2. Fundamental CAM Information from Two Surveys in the U.S.

2.3. Selection of Monographs of Natural Products in this Review

3.1. Preoperative Management for Using of Dietary Supplements

3.2. Commonly Used Herbal Medicines

3.2.7. Green Tea

In a randomized, double-blind, placebo-controlled study, eight subjects received oral EGCG in a

3.2.9. Saw Palmetto

3.2.10. St John’s Wort

3.2.12. Other Herbal Medicines

3.3. Other Commonly Used Dietary Supplements

3.3.1. Coenzyme Q10

Coenzyme Q10 (CoQ10), or ubidecarenone, is a single-constituent antioxidant compound structurally

3.3.2. Glucosamine and Chondroitin Sulfate

3.3.3. Fish Oil

The authors declare that they have no competing interests.

You might also like